The invention relates to novel modulators of the cold-menthol receptor TRPM8, methods for modulation of the TRPM8 receptor using these modulators; use of the modulators to induce a sensation of coldness; and the items and agents produced by use of these modulators.
A specific aspect of the invention relates to an agent comprising at least one selected such modulator for achieving a cooling effect on skin or mucousa, wherein the cooling effect is longer-lasting compared with the known cooling active ingredient menthane-3-carboxylic acid-N-ethyl amide (WS3).
The specific aspect of the invention further relates to agents comprising such selected TRPM8 receptor modulators, wherein the agents serve for particular purposes. Apart from this, the specific aspect of the invention relates to a method for achieving a physiological cooling effect on skin or mucosa, in which the latter agent is used.
The cold menthol receptor TRPM8 (also referred to as Cold Membrane Receptor (CMR)1) belongs to the family of the “Transient Receptor Potential Ion Channels”, is specifically expressed in a special group of neurons and, in the cell membrane, forms pores (in each case 4 units combine to give a tetramer), which selectively allow Ca2+ ions to pass. The protein has 6 transmembrane domains and a cytoplasmatic C and N terminus. Low temperatures (preferably 10-25° C.) stimulate this receptor, resulting in a signal transduction which is interpreted by the nervous system as a sensation of coldness. The receptor was described for the first time in 2002 as cold receptor in a number of publications (Peier A M et al, A TRP channel that senses cold stimuli and menthol. Cell. 2002 Mar. 8; 108(5):705-15; McKemy D D et al. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature. 2002 Mar. 7; 416 (6876): 52-8; Zuker C S, Neurobiology: a cool ion channel. Nature. 2002 Mar. 7; 416 (6876): 27-8).
Cooling compounds, such as e.g. menthol, have for a long time played an important role in the flavourings and fragrance industry in order to produce an association with freshness and cleanliness. For the compound menthol, it has been shown that it acts as a natural modulator of the receptor TRPM8 (McKemy D. D., Molecular Pain 1, 2005, 16; McKemy D. D., Nature 416, 2002, 52-58; Peier A. M., Cell 108, 2002, 705-715; Dhaka A., Annu. Rev. Neurosci. 29, 2006, 135-161). By applying menthol, TRPM8 is activated, which brings about a Ca2+ influx into the cold-sensitive neurons. The electrical signal produced as a result is ultimately perceived as a sensation of coldness. Elevated menthol concentrations lead to irritation and an anaesthetic effect. Moreover, various publications have described menthol derivatives with a similar effect (British Patent 1971#1315761; Watson H. R., J. Soc. Cosmet. Chem. 29, 1978, 185-200; Furrer S. M., Chem. Percept. 1, 2008, 119-126). There are also individual compounds, structurally unrelated to menthol, which bring about a significant TRPM8 modulation, such as e.g. Icilin (Wei E. T., J. Pharm. Pharmacol. 35, 1983, 110-112; WO 2004/026840), WS-23 or compounds listed in the patent application WO 2007/019719.
Further effects of substances which modulate the TRPM8 receptor and/or its insect analogues are a repellent effect on insects (WO 2002/015692; WO 2004/000023, US 2004/0028714), and also activity in antitumor therapy (e.g. an influencing of prostate tumours), activity in the treatment of inflammatory pain/hyperalgesia and an effect as TRPM8 antagonists in the treatment of bladder syndrome or overactive bladder (Beck B. Cell Calcium, 41, 2007, 285-294; Levine J. D. Biochim. Biophys. Acta, Mol. Basis. Dis. 1772, 2007, 989-1003; Mukerji G., BMC Urology 6, 2006, 6; US 2003/0207904; US 2005/6893626, Dissertation Behrendt H. J. 2004, Universitat Bochum; Lashinger E. S. R. Am. J. Physiol. Renal Physiol. Am J Physiol Renal Physiol. 2008 Jun. 18. [Epub ahead of print]; PMID: 18562636).
However, many of the TRPM8 modulators found hitherto have deficiencies with regard to strength of effect, duration of effect, skin/mucosa irritation, odour, taste, solubility and/or volatility.
In the prior international patent application PCT/EP2009/061019 by the applicant with a filing date of 26 Aug. 2009, individual compounds for modulation of the TRPM8 receptor are proposed. These are in detail the following specifically disclosed compounds:
wherein the compound may be present in chemically pure or enriched form, as an individual stereoisomer or in the form of stereoisomer mixtures.
These compounds are known, namely:    Compound 1 under CAS number: 99602-94-5 (3R-cis form)    Compound 2 under CAS number: 165753-08-2    Compound 3 under CAS number: 338771-57-6    Compound 4 under CAS number: 878942-21-3    Compound 5 under CAS number: 748783-13-3 (without stereochemistry)
This specifically disclosed use of compounds 1 to 5 of PCT/EP2009/061019 is expressly excluded from the present application.
PCT/EP2009/061019 further contains the general disclosure that the compounds described there can be present uncharged or in the form of their salts, such as e.g. as acid addition salt. No such salts are specifically disclosed, however.
PCT/EP2009/061019 also contains the general disclosure that in the compounds described there, functional groups may optionally be replaced by equivalent chemical groups; oxygen atoms (such as e.g. ether groups) may thus be replaced by corresponding sulphur groups, and vice versa; keto groups may be replaced by corresponding thionyl groups. No such modifications are specifically disclosed, however.
The disclosure of this international patent application PCT/EP2009/062019 applies herewith, unless in order to make a distinction therefrom it is expressly excluded from the scope of the present invention.